Novel pregnenolone acetonides



United States Patent 3,345,362 NOVEL PREGNENOLONE ACETONIDES Richard T. Rapala, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Filed July 27,1961, Ser. No. 127,115 1 Claim. (Cl. 260-23955) This invention relates to novel steroids. In particular, this invention relates to novel, orally active pregnenolone progestational agents and to the novel pregnenolone intermediates utilized in their manufacture.

At present, progestational agents in orally eifective form are prepared by activating a suitable steroid molecule with one of two groups. One method involves the preparation of the 17a-ethynyl derivative of a testosterone analog, and the other procedure is to attach the 170:- acetoxy substituent to a progestin which is known to be active upon injection. The resulting compounds are, in

general, orally eflective as progestational agents. In each case the compounds also posses a A -3-keto grouping. This grouping and the above substituents, until now, have been obligatory for oral progestational activity.

An object of this invention is to provide novel oral progestational agents which are rendered orally active 'by an entirelydifferent' substituent and, furthermore, in-

C=O CHa O C CH, \0/ CHa These latter compounds possess progestational activity equal to or greater than l7a-acetoxy progesterone and 17-ethynyl-19-nortestosterone, a most unusual fact, since the A and B rings of the new compounds contain the A -3-B-0l group-a structural type not heretofore associated with hormonal action.

The l6a,17a-isopropylidenedioxypregnenolones of this invention are easily derived in two step from a commercially available A -pregnenolone. The preparation generally involves oxidation of a A -pregnenolone to form a 16a,17a-dihydroxypregnenolone, which comprises the novel pregnenolone intermediate of this invention. This intermediate is then converted to the cyclic ketal, i.e., a 16a,17u-isopropylidenedioxypregnenolone, by reaction with acetone and acid. The 16a,l7a-dihydroxypregnenolone and the 16a,17a-dihydroxy-6-methylpregnenolone are preferred intermediates since they readily form, upon reaction with acetone under acidic conditions, the preferred 16a,17a-isopropylidenedioxypregnenolone and the 160; 17oz. isopropylidenedioxy 6 methylpregnenolone progestational agents of this invention. The following illustrative reaction sequence (wherein R is hydrogen or Patented Oct. 3, 1967 ice a methyl group) demonstrates the preparation of the novel l6u,l7a-pregnenolones of this invention:

CH3 C 3 $113 (3H3 0:0 0:0 CH3 l CH KMI104 HO Acetone HO Acetone O CH C o on,

From the above it can be seen that the novel pregnenolones of this invention can be prepared with ease from cheap, readily available starting materials. This fact,

naturally, is of particular significance in steroid chemistry,

which generally involves highly complicated and expensive technology, since it means that the desired steroid medicinal can be marketed at a lower price. This is important in the case of the novel pregnenolones of this invention, since these compounds have a variety of therapeutic applications. For example, the 160:,17oc-iS0- propylidenedioxypregnenolones of this invention, in addition to being excellent progestational agents, also possess anti-infiamatory activity as well asdiuretic action. Likewise, the novel 160,17a-dihydroxypregnenolone intermediates of this invention, not only are excellent chemical intermediates in the synthesis of cyclic ketal and acetals, but also have glucocorticoidal and other biological properties.

The follownig examples more fully demonstrate this inventionparticularly with respect to the ease and simplicity of the preparation of the novel pregnenolones thereof.

Example I This example demonstrates a two-step preparation of 16a,17a-isopropylidenedioxy-6-methylpregnenolone from commercially available 6-methyl-A -pregnenolone. The process proceeds through the novel intermediate, l6a,17otdihydroxy-6-methylpregnenolone.

To a reaction vessel provided with means for cooling and stirring was added 1.0 g. of 6-methyl-A -pregnenolone dissolved in 25 cc. acetone. To this mixture was added 0.25 cc. acetic acid and the resulting solution was cooled in ice, while stirring. Thereafter, a solution of 0.410 g. potassium permanganate in 5 cc. of percent acetone, was added in about one and one-half minutes. The color discharged rapidly. To this mixture was then added sodium bisulfite solution, until the color had completely discharged, after which acetone was added. The resulting mixture was filtered, the filter cake washed with acetone, and the combined filtrate and washings evaporated to a lower volume in vacuo to remove the excess solvent. Water was added as a precipitation aid and, upon further evaporation, a precipitate was produced. The precipitate was cooled, filtered, and recrystallized from aqueous acetone. The crude 16a,17a-dihydroxy-6-methylpregnenolone thus prepared melted at about 138152 C. and weighed 650 mg. The ultraviolet spectrum of an ethanolic solution of this compound showed only about a maximum of 10 percent of the 6-methyl-A -pregnenolone starting material remaining.

To 200 mg. of the above-prepared crystalline 16a,l7adihydroxy-6-methylpregnenolone was added 12 cc. acetone and three drops of concentrated hydrochloric acid. The mixture was maintained at room temperature for about 14 hours, whereupon the desired product, 16a,17aisopropylidenedioxy 6 methylpregnenolone, separated. The resulting slurry was cooled to about C. and filtered. Sixty mg. of product were obtained, melting at 248-25 1 C. This material had no ultraviolet absorption maxima corresponding to the 20 ketone, A unsaturated system,

and the infrared spectrum was consistent with the 160:,17u-

substantiate that the product produced was 16a,l7a-iso- I propylidenedioxy-6-methylpregnenolone.

Example I] The preparation of 16a,l7a-dihydroxypregnenolone and the conversion of this intermediate to 16a,l7m-isopropylidenedioxypregnenolone are demonstrated by the following examples.

To a reaction vessel provided with means for cooling and stirring was added 1.0 g. of A -pregnenolone, dissolved in 45 cc. acetone. To this solution was added 0.25 cc. acetic acid and the resulting solution was cooled in ice while stirring. Thereafter, a solution of 0.410 g. of potassium permanganate in 5 cc. of 85 percent acetone was added in four portions over a period of two minutes. The reaction mixture was allowed to react for an additional one and one-half minutes, and sodium bisulfite solution was thereafter added in sufficient amount to discharge the color of the reaction mixture. The mixture was then filtered and the filtered residue washed with acetone. The filtrate and washings were combined, diluted with water, evaporated in vacuo, and cooled in ice, whereupon a solid 4 precipitate was deposited. After filtration, this precipitate was washed with water and dried in vacuo. The crude 16a,l7a-dihydroxypregnenolone thus prepared melted at 155177 C. and weighed 660 mg. The ultraviolet spectrum of an ethanolic solution of this material showed only about a maximum of 15 percent of the A -pregnenolone remaining. Pure 16a,l7a-dihydroxypregnenolone was prepared by recrystallizing the above material from acetone.

To 200 mg. of the above-prepared, purified 1612,1704- dihydroxypregnenolone were added 12 cc. acetone and four drops of concentrated hydrochloric acid. All the material Went into solution after about 19 hours at room temperature. The solution was then coled to about 0 C. and water was added dropwise. The mixture was allowed to remain at 0 C. for about one hour, and the precipitated material was then filtered. The precipitate, 16a,l7aisopropylidenedioxypregnenolone, was washed and then vacuum dried. The material thus obtained weighed mg. and melted at 193-200 C. There was no ultravioletabsorbing impurity present, and the infrared spectrum was consistent with the 16a,17a-isopropylidenedioxyprcgnenolone structure.

For convenience, the compounds of this invention have been named as pregnenolone derivatives; that is, derivatives of 3fi-hydroxy-S-pregnen-Z0-one. However, l6a,l7adihydroxypregnenolone could also be named 3,B-l6a,17atrihydroxy-5-pregnen-20-one, and 16a,l7a-isopropylidenedioxy-6-methylpregnenolone could be called 16a,l7otisopropylidenedioxy 6 methyl 3B hydroxy 5 pregnen-20-one.

I claim:

16a,17a-isopropylidenedioxy-6-methylpregnenolone.

References Cited UNITED STATES PATENTS 2,727,909 12/1955 Colton 260397.4 2,941,997 6/1960 Fried 260-23955 3,021,345 2/1962 Feather et al. 260397.4

ELBERT L. ROBERTS, Primary Examiner.

L. GO'ITS, M. LIEBMAN, E. ROBERTS, G. E. LANDE,

Assistant Examiners. 

